Unveiling Hierarchical Self-Assembly of Triazolylferrocenyl Dendrimers: Producing Non-Traditional Intrinsically Green Fluorescent Vesosomes for Nanotheranostics.

Dendrimers and supramolecular chemistry continue to fascinate researchers due to the endless unrevealed potential of their combination. This study investigates the self-assembly process of a series of hydrophobic triazolylferrocenyl dendrimers in aqueous medium. Deep investigation through NMR spectroscopy, absorption UV-vis spectroscopy along with theoretical simulations demonstrates that the ferrocenyl moieties interact intramolecularly and intermolecularly driving the self-assembly process. Data obtained by DLS, NTA, SEM, TEM, and EF-TEM demonstrate that these dendrimers, in water, spontaneously self-assemble through a hierarchical process. The dendrimers first self-assemble into uniform nanovesicles, which in turn self-assemble into larger vesosomes. The resulting vesosomes emit green non-traditional intrinsic fluorescence, which is a property that emerged from the self-assembled architectures. The vesosomes are efficiently uptaken by cancer cells and induce significant cytotoxic activity against the cancer cell line MCF-7, up to the submicromolar concentration. Positive dendritic effects are identified in the fluorescence intensity and in the cytotoxic activity of the vesosomes, which follow the trend G0-9Fc < G1-27Fc < G2-81Fc. This work showcases the remarkable potential of combining the two dynamic fields of dendrimers and supramolecular chemistry, which resulted in green fluorescent vesosomes capable of performing the dual role of cell imaging and killing, with potential applications in nanotheranostics.

Longitudinal Trajectories of Estimated Glomerular Filtration Rate in a European Population of Living Kidney Donors.

A living donor (LD) kidney transplant is the best treatment for kidney failure, but LDs safety is paramount. We sought to evaluate our LDs cohort's longitudinal changes in estimated glomerular filtration rate (eGFR). We retrospectively studied 320 LDs submitted to nephrectomy between 1998 and 2020. The primary outcome was the eGFR change until 15 years (y) post-donation. Subgroup analysis considered distinct donor characteristics and kidney function reduction rate (%KFRR) post-donation [-(eGFR6 months(M)-eGFRpre-donation)/eGFRpre-donation*100]. Donors had a mean age of 47.3 ± 10.5 years, 71% female. Overall, LDs presented an average eGFR change 6 M onward of +0.35 mL/min/1.73 m2/year. The period with the highest increase was 6 M-2 Y, with a mean eGFR change of +0.85L/min/1.73 m2/year. Recovery plateaued at 10 years. Normal weight donors presented significantly better recovery of eGFR +0.59 mL/min/1.73 m2/year, compared to obese donors -0.18L/min/1.73 m2/year (p = 0.020). Noteworthy, these results only hold for the first 5 years. The subgroup with a lower KFRR (<26.2%) had a significantly higher decrease in eGFR overall of -0.21 mL/min/1.73 m2/year compared to the groups with higher KFRR (p < 0.001). These differences only hold for 6 M-2 Y. Moreover, an eGFR<50 mL/min/1.73 m2 was a rare event, with ≤5% prevalence in the 2-15 Y span, correlating with eGFR pre-donation. Our data show that eGFR recovery is significant and may last until 10 years post-donation. However, some subgroups presented more ominous kidney function trajectories.

Fosfatriclaben: Effective dose determination and comparative efficacy assessment with closantel, triclabendazole+ivermectin, triclabendazole+albendazole in artificially infected cattle.

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.

Bacterial cell cycle regulator MatP forms biomolecular condensates and directly interacts with cell division protein FtsZ.

Bacterial cytokinesis is driven by a contractile ring of FtsZ protein polymers at midcell. FtsZ can also form phase-separated biomolecular condensates with potential implications for cytokinesis and development of antibiotic-tolerant persister cells. In Escherichia coli , FtsZ ring positioning depends in part on the MatP protein, which binds DNA sites ( matS ) in the chromosome terminus region and indirectly interacts with FtsZ through two other proteins. We report here that MatP also forms biomolecular condensates in reconstituted systems that mimic the crowded bacterial cytoplasm, on its own or with FtsZ. Our biophysical analyses uncover a direct MatP-FtsZ interaction, which is disrupted by matS sites that also regulate MatP condensate formation. These condensates preferentially locate at the surface of lipid droplets, a behavior probably mediated by MatP-lipid binding. GTP triggers assembly of FtsZ polymers from FtsZ-MatP condensates. These polymers are decorated with MatP, but exposure to matS sites releases MatP. Such matS -responsive MatP biomolecular condensates, regulated by GTP when coassembled with FtsZ, may provide a mechanism for MatP storage and rapid mobilization that could facilitate MatP's role in spatially regulating cytokinesis. Moreover, sequestration of MatP through phase separation could promote cell entry into dormant states that are able to survive antibiotic treatments.

New Origins of Yeast, Plant and Bacterial-Derived Extracellular Vesicles to Expand and Advance Compound Delivery.

Extracellular vesicles (EVs) constitute a sophisticated molecular exchange mechanism highly regarded for their potential as a next-generation platform for compound delivery. However, identifying sustainable and biologically safe sources of EVs remains a challenge. This work explores the emergence of novel sources of plant and bacterial-based EVs, such as those obtained from food industry by-products, known as BP-EVs, and their potential to be used as safer and biocompatible nanocarriers, addressing some of the current challenges of the field. These novel sources exhibit remarkable oral bioavailability and biodistribution, with minimal cytotoxicity and a selective targeting capacity toward the central nervous system, liver, and skeletal tissues. Additionally, we review the ease of editing these recently uncovered nanocarrier-oriented vesicles using common EV editing methods, examining the cargo-loading processes applicable to these sources, which involve both passive and active functionalization methods. While the primary focus of these novel sources of endogenous EVs is on molecule delivery to the central nervous system and skeletal tissue based on their systemic target preference, their use, as reviewed here, extends beyond these key applications within the biotechnological and biomedical fields.

Unveiling Transcriptional and Epigenetic Mechanisms Within Engram Cells: Insights into Memory Formation and Stability.

Memory traces for behavioral experiences, such as fear conditioning or taste aversion, are believed to be stored through biophysical and molecular changes in distributed neuronal ensembles across various brain regions. These ensembles are known as engrams, and the cells that constitute them are referred to as engram cells. Recent advancements in techniques for labeling and manipulating neural activity have facilitated the study of engram cells throughout different memory phases, including acquisition, allocation, long-term storage, retrieval, and erasure. In this chapter, we will explore the application of next-generation sequencing methods to engram research, shedding new light on the contribution of transcriptional and epigenetic mechanisms to engram formation and stability.

Amitraz Resistance in French Varroa Mite Populations-More Complex Than a Single-Nucleotide Polymorphism.

Resistance against amitraz in Varroa mite populations has become a subject of interest in recent years due to the increasing reports of the reduced field efficacy of amitraz treatments, especially from some beekeepers in France and the United States. The loss of amitraz as a reliable tool to effectively reduce Varroa mite infestation in the field could severely worsen the position of beekeepers in the fight to keep Varroa infestation rates in their colonies at low levels. In this publication, we present data from French apiaries, collected in the years 2020 and 2021. These data include the field efficacy of an authorized amitraz-based Varroa treatment (Apivar® ,Véto-pharma, France) and the results of laboratory sensitivity assays of Varroa mites exposed to the reference LC90 concentration of amitraz. In addition, a total of 240 Varroa mites from Eastern, Central, and Southern regions in France that were previously classified as either "sensitive" or "resistant" to amitraz in a laboratory sensitivity assay were genotyped. The genetic analyses of mite samples are focused on the ß-adrenergic-like octopamine receptor, which is considered as the main target site for amitraz in Varroa mites. Special attention was paid to a single-nucleotide polymorphism (SNP) at position 260 of the ORß-2R-L gene that was previously associated to amitraz resistance in French Varroa mites, Varroa. Our findings confirm that amitraz resistance occurs in patches or "islands of resistance", with a less severe reduction in treatment efficacy compared to pyrethroid resistance or coumaphos resistance in Varroa mites. The results of our genetic analyses of Varroa mites call into question the hypothesis of the SNP at position 260 of the ORß-2R-L gene being directly responsible for amitraz resistance development.

The Effects of Head Elevation on Intracranial Pressure, Cerebral Perfusion Pressure, and Cerebral Oxygenation Among Patients with Acute Brain Injury: A Systematic Review and Meta-Analysis.

BACKGROUND: Head elevation is recommended as a tier zero measure to decrease high intracranial pressure (ICP) in neurocritical patients. However, its quantitative effects on cerebral perfusion pressure (CPP), jugular bulb oxygen saturation (SjvO2), brain tissue partial pressure of oxygen (PbtO2), and arteriovenous difference of oxygen (AVDO2) are uncertain. Our objective was to evaluate the effects of head elevation on ICP, CPP, SjvO2, PbtO2, and AVDO2 among patients with acute brain injury. METHODS: We conducted a systematic review and meta-analysis on PubMed, Scopus, and Cochrane Library of studies comparing the effects of different degrees of head elevation on ICP, CPP, SjvO2, PbtO2, and AVDO2. RESULTS: A total of 25 articles were included in the systematic review. Of these, 16 provided quantitative data regarding outcomes of interest and underwent meta-analyses. The mean ICP of patients with acute brain injury was lower in group with 30° of head elevation than in the supine position group (mean difference [MD] - 5.58 mm Hg; 95% confidence interval [CI] - 6.74 to - 4.41 mm Hg; p < 0.00001). The only comparison in which a greater degree of head elevation did not significantly reduce the ICP was 45° vs. 30°. The mean CPP remained similar between 30° of head elevation and supine position (MD - 2.48 mm Hg; 95% CI - 5.69 to 0.73 mm Hg; p = 0.13). Similar findings were observed in all other comparisons. The mean SjvO2 was similar between the 30° of head elevation and supine position groups (MD 0.32%; 95% CI - 1.67% to 2.32%; p = 0.75), as was the mean PbtO2 (MD - 1.50 mm Hg; 95% CI - 4.62 to 1.62 mm Hg; p = 0.36), and the mean AVDO2 (MD 0.06 µmol/L; 95% CI - 0.20 to 0.32 µmol/L; p = 0.65).The mean ICP of patients with traumatic brain injury was also lower with 30° of head elevation when compared to the supine position. There was no difference in the mean values of mean arterial pressure, CPP, SjvO2, and PbtO2 between these groups. CONCLUSIONS: Increasing degrees of head elevation were associated, in general, with a lower ICP, whereas CPP and brain oxygenation parameters remained unchanged. The severe traumatic brain injury subanalysis found similar results.

Light competition drives species replacement during secondary tropical forest succession.

Light competition is thought to drive successional shifts in species dominance in closed vegetations, but few studies have assessed this for species-rich and vertically structured tropical forests. We analyzed how light competition drives species replacement during succession, and how cross-species variation in light competition strategies is determined by underlying species traits. To do so, we used chronosequence approach in which we compared 14 Mexican tropical secondary rainforest stands that differ in age (8-32 year-old). For each tree, height and stem diameter were monitored for 2 years to calculate relative biomass growth rate (RGR, the aboveground biomass gain per unit aboveground tree biomass per year). For each stand, 3D light profiles were measured to estimate individuals' light interception to calculate light interception efficiency (LIE, intercepted light per unit biomass per year) and light use efficiency (LUE, biomass growth per intercepted light). Throughout succession, species with higher RGR attained higher changes in species dominance and thus increased their dominance over time. Both light competition strategies (LIE and LUE) increased RGR. In early succession, a high LIE and its associated traits (large crown leaf mass and low wood density) are more important for RGR. During succession, forest structure builds up, leading to lower understory light levels. In later succession, a high LUE and its associated traits (high wood density and leaf mass per area) become more important for RGR. Therefore, successional changes in relative importance of light competition strategies drive shifts in species dominance during tropical rainforest succession.

Impact of hyponatremia in patients hospitalized in Internal Medicine units: Hyponatremia in Internal Medicine units.

The aim of this study was to analyze the impact and the clinical and evolutionary characteristics of hypotonic hyponatremia in patients hospitalized in Internal Medicine units. Prospective multicenter observational study of patients with hypotonic hyponatremia (<135 mmol/L) in 5 hospitals in southern Spain. Patients were included according to point prevalence studies carried out every 2 weeks between March 2015 and October 2017, by assessing demographic, clinical, analytical, and management data; each patient was subsequently followed up for 12 months, during which time mortality and readmissions were assessed. A total of 501 patients were included (51.9% women, mean age = 71.3 ±â€…14.24 years), resulting in an overall prevalence of hyponatremia of 8.3%. The mean comorbidities rate was 4.50 ±â€…2.41, the most frequent diagnoses being heart failure (115) (23%), respiratory infections (65) (13%), and oncological pathologies (42) (6.4%). Of the total number of hyponatremia cases, 180 (35.9%) were hypervolemic, 164 (32.7%) hypovolemic, and 157 (31.3%) were euvolemic. A total of 87.4% did not receive additional diagnostic tests to establish the origin of the condition and 30% did not receive any treatment. Hospital mortality was 15.6% and the mean length of stay was 14.7 days. Euvolemic and admission hyponatremia versus hyponatremia developed during admission were significantly associated with lower mortality rates (P = .037). Mortality at 1 year and readmissions were high (31% and 53% of patients, respectively). Hyponatremia was common in Internal Medicine areas, with hypervolemic hyponatremia being the most frequent type. The mortality rate was high during admission and at follow-up; yet there is a margin for improvement in the clinical management of this condition.

Neuropsychological outcomes in patients with ruptured anterior communicating artery aneurysms treated by clipping versus coiling: a systematic review and meta-analysis.

Ruptured anterior communicating artery (ACoA) aneurysms are frequently associated with neuropsychological deficits. This review aims to compare neuropsychological outcomes between surgical and endovascular approaches to ACoA. We systematically searched PubMed, Embase, and Web of Science for studies comparing the endovascular and surgical approaches to ruptured ACoA aneurysms. Outcomes of interest were the cognitive function, covered by memory, attention, intelligence, executive, and language domains, as well as motor and visual functions. Nine studies, comprising 524 patients were included. Endovascularly-treated patients showed better memory than those treated surgically (Standardized Mean Difference (SMD) = -2; 95% CI: -3.40 to -0.61; p < 0.01). Surgically clipped patients had poorer motor ability than those with coiling embolization (p = 0.01). Executive function (SMD = -0.20; 95% CI: -0.47 to 0.88; p = 0.55), language (SMD = -0.33; 95% CI: -0.95 to 0.30; p = 0.30), visuospatial function (SMD = -1.12; 95% CI: -2.79 to 0.56; p = 0.19), attention (SMD = -0.94; 95% CI: -2.79to 0.91; p = 0.32), intelligence (SMD = -0.25; 95% CI: -0.73 to 0.22; p = 0.30), and self-reported cognitive status (SMD = -0.51; 95% CI: -1.38 to 0.35; p = 0.25) revealed parity between groups. Patients with ACoA treated endovascularly had superior memory and motor abilities. Other cognitive domains, including executive function, language, visuospatial function, attention, intelligence and self-reported cognitive status revealed no statistically significant differences between the two approaches. Trial Registration PROSPERO (International Prospective Register of Systematic Reviews) CRD42023461283; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=461283.

Variety Is the Spice of Life: Diverse Social Networks Are Associated With Social Cohesion and Well-Being.

Both homophily and heterophily are observed in humans. Homophily reinforces homogeneous social networks, and heterophily creates new experiences and collaborations. However, at the extremes, high levels of homophily can cultivate prejudice toward out-groups, whereas high levels of heterophily can weaken in-group support. Using data from 24,726 adults (M = 46 years; selected from 10,398 English neighborhoods) and the composition of their social networks based on age, ethnicity, income, and education, we tested the hypothesis that a middle ground between homophily and heterophily could be the most beneficial for individuals. We found that network homophily, mediated by perceived social cohesion, is associated with higher levels of subjective well-being but that there are diminishing returns, because at a certain point increasing network homophily is associated with lower social cohesion and, in turn, lower subjective well-being. Our results suggest that building diverse social networks provides benefits that cannot be attained by homogeneous networks.

Deconstructing neutrophil to lymphocyte ratio (NLR) in early breast cancer: lack of prognostic utility and biological correlates across tumor subtypes.

PURPOSE: The prognostic utility and biological correlates of neutrophil to lymphocyte ratio (NLR), a potential biomarker of the balance between immune response and the inflammatory status, are still uncertain in breast cancer (BC). METHODS: We analysed a cohort of 959 women with early breast cancer, mostly treated with neoadjuvant or adjuvant chemotherapy. Clinical and pathological data, survival, NLR (continuous and categorical) and stromal tumor infiltrating lymphocytes (sTIL) were evaluated. RESULTS: NLR was only weakly associated with Ki67, while no association was found for grade, histology, immunohistochemical subtype or stage. Lymphocyte infiltration of the tumor did not correlate with NLR (Rho: 0.05, p = 0.30). These results were similar in the whole group and across the different BC subtypes, with no differences in triple negative BC. Relapse free interval (RFI), breast cancer specific survival (BCSS) and overall survival (OS) changed according to pre-treatment NLR neither in the univariate nor in the multivariate Cox models (RFI: HR 0.948, p = 0.61; BCSS: HR 0.920, p = 0.57; OS: HR 0.96, p = 0.59). CONCLUSION: These results question the utility of NLR as a prognostic biomarker in early breast cancer and suggest the lack of correlation of NLR with tumor microenvironment immune response.

Nephrectomy with Autotransplantation-A Key Treasure.

Background: Nephrectomy with autotransplantation (NAT) has been performed as an alternative treatment for complex renovascular lesions, intricate ureteral strictures and nephron-sparing surgery in complex renal tumors. Methods: A retrospective observational study was conducted including patients who underwent a NAT from January 2010 to September 2023. Data collected included surgery indications, surgical technique, complications according to Clavien-Dindo classification and mean hospital stay. Descriptive and inferential statistical analysis was performed using IBM® SPSS® Statistics version 28.0.1.0. Results: A total of 34 consecutive patients underwent 38 NATs at our institution. Surgery indications were complex renovascular conditions in 35 cases (92.1%), of which 24 had renal artery aneurysms, and ureteral injuries in 3 cases (7.9%). Thirty-four kidneys (89.5%) were retrieved through a laparoscopic approach. No significant difference was observed between post- and pre-operative creatinine levels (0.81 vs. 0.72, p = 0.303). Early high-grade complications developed in 12 procedures (31.6%). Median cold ischemia time was significantly longer in patients who developed complications (163.0 vs. 115.0, p = 0.010). The median hospital stay was 10 days (8-13). The median follow-up was 51.5 months. Conclusions: NAT emerges as a successful therapeutic strategy for a highly select group of patients dealing with intricate ureteral lesions and kidney vascular abnormalities, demonstrating positive outcomes that endure in the long term.

Clinical performance of the iPREDICTLIVING tool for the prediction of the post-transplant recipient and living donor outcomes in a European cohort.

A living donor kidney transplant (LDKT) is the best treatment for ESRD. A prediction tool based on clinical and demographic data available pre-KT was developed in a Norwegian cohort with three different models to predict graft loss, recipient death, and donor candidate's risk of death, the iPREDICTLIVING tool. No external validations are yet available. We sought to evaluate its predictive performance in our cohort of 352 pairs LKDT submitted to KT from 1998 to 2019. The model for censored graft failure (CGF) showed the worse discriminative performance with Harrell's C of .665 and a time-dependent AUC of .566, with a calibration slope of .998. For recipient death, at 10 years, the model had a Harrell's C of .776, a time-dependent AUC of .773, and a calibration slope of 1.003. The models for donor death were reasonably discriminative, although with a poor calibration, particularly for 20 years of death, with a Harrell's C of .712 and AUC of .694 with a calibration slope of .955. These models have moderate discriminative and calibration performance in our population. The tool was validated in this Northern Portuguese cohort, Caucasian, with a low incidence of diabetes and other comorbidities. It can improve the informed decision-making process at the living donor consultation joining clinical and other relevant information.

Transperitoneal vs. Retroperitoneal Approach in Laparoscopic Partial Nephrectomy for Posterior Renal Tumors: A Retrospective, Multi-Center, Comparative Study.

Purpose: The aim of our study is to compare the perioperative, functional, and oncological outcomes of laparoscopic transperitoneal partial nephrectomy (LTPN) and laparoscopic retroperitoneal partial nephrectomy (LRPN) for posterior cT1 renal tumors. Methods: We retrospectively collected data on all patients who consecutively underwent LTPN and LRPN for posterior cT1 renal tumors in three different centers from January 2015 to January 2023. Patients with a single, unilateral, cT1 renal mass, located in the posterior renal surface were included. Patients' data regarding perioperative, functional, and oncological outcomes were collected from medical records and statistically analyzed and compared. Results: A total of 128 patients was obtained, with 53 patients in the LPTN group and 75 patients in the LRPN group. Baseline characteristics were similar. Warm ischemia time (WIT) (18.8 vs. 22.6 min, p = 0.002) and immediate postoperative eGFR drop (-6.1 vs. -13.0 mL/min/1.73 m2, p = 0.047) were significantly lower in the LPTN group. Estimated blood loss (EBL) (100 vs. 150 mL, p = 0.043) was significantly lower in the LRPN group. All other perioperative and functional outcomes and complications were similar between the groups. The positive surgical margin (PSM) rate was lower in the LRPN group, although without statistical significance (7.2% vs. 13.5%, p = 0.258). Surgical success defined by Trifecta (WIT ≤ 25 min, no PSM, and no major postoperative complication) was similar between both approaches. Conclusions: LTPN has significantly shorter WIT and a significantly smaller drop in immediate eGFR when compared to LRPN for posterior renal tumors. On the other hand, LRPN has significantly less EBL than LTPN. LRPN demonstrated fewer PSMs than LTPN, albeit without statistical significance. In terms of overall surgical success, as defined by Trifecta, both approaches achieved similar results.

Effect of antipsychotic drugs on group II metabotropic glutamate receptor expression and epigenetic control in postmortem brains of schizophrenia subjects.

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu2R and mGlu3R) in brains of schizophrenia patients may explain the limited efficacy of mGlu2/3R ligands in clinical trials. Studies evaluating mGlu2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu2R and mGlu3R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu2R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu3R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D2 and serotonin 5HT2A receptors correlated with higher density of mGlu3R, but not mGlu2R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu2R, but not mGlu3R regulation observed in schizophrenia brains. mGlu2R and mGlu3R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu2R and mGlu3R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu3R, but not mGlu2R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu3R expression are activated to counterbalance mGluR loss of function is described.

Permissive epigenetic regulatory mechanisms at the histone level are enhanced in postmortem dorsolateral prefrontal cortex of individuals with schizophrenia.

BACKGROUND: Susceptibility to schizophrenia is determined by interactions between genes and environment, possibly via epigenetic mechanisms. Schizophrenia has been associated with a restrictive epigenome, and histone deacetylase (HDAC) inhibitors have been postulated as coadjuvant agents to potentiate the efficacy of current antipsychotic drugs. We aimed to evaluate global histone posttranslational modifications (HPTMs) and HDAC expression and activity in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. METHODS: We used postmortem DLPFC samples of individuals with schizophrenia and controls matched for sex, age, and postmortem interval. Schizophrenia samples were classified into antipsychotic-treated or antipsychotic-free subgroups according to blood toxicology. Expression of HPTMs and HDAC was quantified by Western blot. HDAC activity was measured with a fluorometric assay. RESULTS: H3K9ac, H3K27ac, and H3K4me3 were globally enhanced in the DLPFC of individuals with schizophrenia (+24%-42%, p < 0.05). HDAC activity (-17%, p < 0.01) and HDAC4 protein expression (-20%, p < 0.05) were downregulated in individuals with schizophrenia. Analyses of antipsychotic-free and antipsychotic-treated subgroups revealed enhanced H3K4me3 and H3K27ac (+24%-49%, p < 0.05) and reduced HDAC activity in the antipsychotic-treated, but not in the antipsychotic-free subgroup. LIMITATIONS: Special care was taken to control the effect of confounding factors: age, sex, postmortem interval, and storage time. However, replication studies in bigger cohorts might strengthen the association between permissive HPTMs and schizophrenia. CONCLUSION: We found global HPTM alterations consistent with an aberrantly permissive epigenome in schizophrenia. Further studies to elucidate the significance of enhanced permissive HPTMs in schizophrenia and its association with the mechanism of action of antipsychotic drugs are encouraged.

Repercussions of the Emergency neurological life support on scientific literature: a bibliometric study.

BACKGROUND: In 2012, the Neurocritical Care Society launched a compilation of protocols regarding the core issues that should be addressed within the first hours of neurological emergencies - the Emergency neurological life support (ENLS). OBJECTIVE: We aim to evaluate this repercussion through a bibliometric analysis. METHODS: We searched Scopus on October 2022 for articles mentioning ENLS. The following variables were obtained: number of citations; number of citations per year; number of publications per year; year of publication; research type; research subtype; country of corresponding author and its income category and world region; journal of publication and its 5-year impact factor (IF); and section where ENLS appeared. RESULTS: After applying eligibility criteria, we retrieved 421 articles, published from 2012 to 2022. The mean number of citations per article was 17.46 (95% Confidence Interval (CI) = 8.20-26.72), while the mean number of citations per year per article was 4.05 (95% CI = 2.50-5.61). The mean destiny journal 5-year IF was 5.141 (95% CI = 4.189-6.093). The majority of articles were secondary research (57.48%; n = 242/421) of which most were narrative reviews (71.90%; n = 174/242). High-Income countries were the most prominent (80.05%; n = 337/421 articles). There were no papers from low-income countries. There were no trials or systematic reviews from middle-income countries. CONCLUSION: Although still low, the number of publications mentioning ENLS is increasing. Articles were mainly published in journals of intensive care medicine, neurology, neurosurgery, and emergency medicine. Most articles were published by authors from high-income countries. The majority of papers were secondary research, with narrative review as the most frequent subtype.

ANTECEDENTES: Em 2012, a Neurocritical Care Society lançou uma compilação de protocolos sobre as questões centrais que devem ser abordadas nas primeiras horas de emergências neurológicas ­ Emergency neurological life support (ENLS). OBJETIVO: Avaliar a repercussão do ENLS por meio de uma análise bibliométrica. MéTODOS: A base de dados Scopus foi utilizada em outubro de 2022 para a busca por artigos mencionando o ENLS. As seguintes variáveis foram obtidas: número de citações; número de citações por ano; número de publicações por ano; ano de publicação; tipo de pesquisa; país do autor correspondente e sua categoria de renda; revista de publicação e seu fator de impacto de 5 anos (IF); e seção onde o ENLS apareceu. RESULTADOS: Os 421 artigos incluídos foram publicados de 2012 a 2022. A média de citações por artigo foi de 17.46 (intervalo de confiança (IC) 95% = 8.20­26.72), enquanto a de citações por ano por artigo foi de 4.05 (IC95% = 2.50­5.61). O IF médio por revista foi de 5.14 (IC95% = 4.19­6.09). A maioria dos artigos era de pesquisa secundária (57.48%; n = 242/421), dos quais a maioria eram revisões narrativas (71.90%; n = 174/242). Os países de alta renda foram os mais prolíficos (80.05%; n = 337/421 artigos). Não houve publicações de países de baixa ou média renda. CONCLUSãO: Embora ainda baixo, o número de publicações mencionando o ENLS vem aumentando recentemente. A maioria dos artigos foram publicados em revistas de medicina intensiva, neurologia, neurocirurgia e medicina de emergência. Artigos de pesquisa secundária foram os mais comuns, com revisões narrativas sendo o subtipo mais frequente.